Preparation and use of crystalline beta-D-nicotinamide riboside

Patent metadata

Field	Value
Publication number	US-10316054-B2
Application number	US-201515315068-A
Country	US
Kind code	B2
Filing date	Jun 2, 2015
Priority date	Jun 2, 2014
Publication date	Jun 11, 2019
Grant date	Jun 11, 2019

Abstract

Provided herein are crystalline beta-D-nicotinamide riboside chloride compositions and methods of preparation and use thereof. Also provided are related pharmaceutical compositions and methods of use thereof. The crystalline beta-D-nicotinamide riboside chloride compositions may be used to treat a disease or disorder that would benefit from increased NAD levels including a mitochondrial disease or disorder, insulin resistance, a metabolic syndrome, diabetes, obesity, or for increasing insulin sensitivity in a subject.

First claim

What is claimed is:

1. A substantially isomerically pure 3-carbamoyl-1-((2R,3R,4S,5R)-3,4-dihydroxy-5 (hydroxymethyl)tetrahydrofuran-2-yl)pyridin-1-ium (β-D-nicotinamide riboside (or 2R (β) nicotinamide riboside)) chloride crystal of greater than 90% chemical purity (w/w) containing <5000 ppm ethanol and <1000 ppm other solvents.

2. A substantially isomerically pure 3-carbamoyl-1-((2R,3R,4S,5R)-3,4-dihydroxy-5 (hydroxymethyl)tetrahydrofuran-2-yl)pyridin-1-ium (β-D-nicotinamide riboside (or 2R (β) nicotinamide riboside)) chloride methanolate crystal of greater than 90% chemical purity (w/w) containing between 0.01 and 1.1 molar equivalent of methanol and <1000 ppm other solvents.

3. The substantially isomerically pure 3-carbamoyl-1-((2R,3R,4S,5R)-3,4-dihydroxy-5 (hydroxymethyl)tetrahydrofuran-2-yl)pyridin-1-ium (β-D-nicotinamide riboside) chloride methanolate crystal of claim 2 containing between 0.7 and 1.1 molar equivalent of methanol.

4. The substantially pure β-D-nicotinamide riboside (2R (β) nicotinamide riboside) chloride crystal of claim 1 , comprising less than 1% (m/m) of 3-carbamoyl-1-((2S,3R,4S,5R)-3,4-dihydroxy-5 (hydroxymethyl)tetrahydrofuran-2-yl)pyridin-1-ium (2S (α) nicotinamide riboside) chloride.

5. The substantially isomerically pure β-D-nicotinamide riboside (2R (β) nicotinamide riboside) chloride crystal of claim 1 having a chemical purity of greater than 95% (w/w).

6. The substantially isomerically pure β-D-nicotinamide riboside (2R (β) nicotinamide riboside) chloride crystal of claim 1 , having a chemical purity greater than or equal to 99% (w/w).

7. The substantially isomerically pure β-D-nicotinamide riboside (2R (β) nicotinamide riboside) chloride crystal of claim 1 , containing <4000 ppm ethanol.

8. The substantially isomerically pure β-D-nicotinamide riboside (2R (β) nicotinamide riboside) chloride crystal of claim 1 , containing a level of ethanol selected from the group consisting of 0-100 ppm ethanol, 100-200 ppm ethanol, 200-300 ppm ethanol, 300-400 ppm ethanol, and 400-500 ppm ethanol.

9. The substantially isomerically pure β-D-nicotinamide riboside (2R (β) nicotinamide riboside) chloride crystal of claim 1 , having an X-ray powder diffraction pattern as shown in FIG. 6 .

10. The substantially isomerically pure β-D-nicotinamide riboside (2R (β) nicotinamide riboside) chloride crystal of claim 1 , having four or more of the following X-ray powder diffraction peaks: about 14.2, about 17.1, about 20.5, about 22.7, about 23.8, about 25.1, about 26.8, and about 34.2 degrees.

11. The substantially isomerically pure β-D-nicotinamide riboside (2R (β) nicotinamide riboside) chloride crystal of claim 1 , having an infrared absorption spectrum as shown in FIG. 8 .

12. The substantially isomerically pure β-D-nicotinamide riboside (2R (β) nicotinamide riboside) chloride crystal of claim 1 , having an IR spectrum comprising peaks at (cm −1 ) 3299, 1700, 1398, 1080, 982, 887, and 795.

13. The substantially isomerically pure β-D-nicotinamide riboside (2R (β) nicotinamide riboside) chloride methanolate crystal of claim 2 , having an X-ray powder diffraction pattern as shown in FIG. 4 .

14. The substantially isomerically pure β-D-nicotinamide riboside (2R (β) nicotinamide riboside) chloride methanolate crystal of claim 2 , having five or more of the following X-ray powder diffraction peaks (degrees): about −11.1, about −7.1, about −2.9, about 1.0, about 4.7, about 15.2, about 18.2, about 21.4, about 23.5, about 24.9, about 26.0, and about 27.7 degrees.

15. The substantially isomerically pure β-D-nicotinamide riboside (2R (β) nicotinamide riboside) methanolate crystal of claim 2 , having an infrared absorption spectrum as shown in FIG. 7 .

16. The substantially isomerically pure β-D-nicotinamide riboside (2R (β) nicotinamide riboside) methanolate crystal of claim 2 , having an infrared absorption spectrum comprising peaks at (cm −1 ) 3361, 1674, 1610, 1394, 1082, 982, 833, and 792.

17. A pharmaceutical composition comprising a β D-nicotinamide riboside (2R (β) nicotinamide riboside) chloride crystal of claim 1 .

18. The pharmaceutical composition of claim 17 , wherein the pharmaceutical composition is for intranasal, dermal, urogenital, ophthalmic, otologic, or respiratory inhalation administration.

19. A method of preparing an aqueous solution of 3-carbamoyl-1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyridin-1-ium (2R (β) nicotinamide riboside) chloride comprising providing a crystalline 3-carbamoyl-1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyridin-1-ium (2R (β) nicotinamide riboside) chloride, and contacting the crystalline 2R (β) nicotinamide riboside chloride with water.

20. A method of treating a disease or disorder that would benefit from increased NAD levels comprising administering a pharmaceutical composition of claim 17 .

Assignees

• Glaxosmithkline Ip No 2 Ltd

Inventors

• Szczepankiewicz Bruce G
• Koppetsch Karsten
• Perni Robert B

Classifications

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P7/02

  Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P3/06

  Antihyperlipidemics · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title